Patent GB-800006-A (GB)
Title: Improvements in the production of compounds of the pyrimidine series
Filed: 1956-05-30
Abstract: Pyrimidine compounds of the general formula <FORM:0800006/IV (b)/1> in which X and Y are hydrogen atoms or organic radicals, and R is a hydrogen atom or an alkyl, aryl, sulph-hydryl, amino, alkylamino, arylamino, acylamino, or sulphonamido group, are prepared by the addition of an aromatic hydroxy compound to an a -acetylene aldehyde or ketone in the presence of a basic agent, e.g. NaOH, tertiary amines, and then reacting the resultant b -aryloxyvinyl-a -aldehyde or -ketone with a compound of formula R.C(: NH)NH2 or a salt thereof. Specified a -acetylene aldehydes and ketones are propargylaldehyde, butine-1-one-3, pentine-2-one-4, 3-phenylpropine-1-one-3, 1-phenylbutine-1-one-3, and heptine-2-al-1; and in the above general formula X and Y are hydrogen atoms when acetylene aldehyde itself is used, either X or Y represents an organic radical when an acetylene ketone or an acetylene-1-aldehyde substituted in the 3-position by an organic radical is used, and both X and Y are organic radicals when an acetylene-1-ketone substituted in the 3-position by an organic radical is used.  Specified aromatic hydroxy compounds include phenol, cresols, xylenols, naphthols, and their halogen, nitro, hydroxy and/or dimethylamino derivatives, and the reaction is effected in solution or dispersion in inert solvents, e.g. water, alcohols, hydrocarbons or ethers.  Specified amidines R.C(: NH)NH2 for the second stage of the process include formamidine, acetamidine, benzamidine, thiourea, p-amino- and p-acetylamino-benzene sulphonyl guanidine, methyl-, phenyl- and acetyl-guanidine and their salts, the reaction with the b -aryloxyvinyl aldehyde or ketone being preferably effected in aqueous or alcoholic medium in the presence of a condensing agent, e.g. alkali metal hydrides, or alcoholates, or 80 to 100 per cent sulphuric acid.  In examples: (1) propargylaldehyde vapour (from CrO3H2SO4 oxidation of propargyl alcohol) is led into a solution of phenol in water containing pyridine or triethylamine, the aqueous layer separated and the dried organic layer fractionated to yield b -phenoxyacrolein, which is then run into a cooled, stirred solution of guanidine carbonate in aqueous sodium hydroxide, more alkali is added and 2-aminopyridine isolated from the mixture by extraction with methylene chloride; (2) as in (1) but using guanidine hydrochloride; alternative aldehydes are b -(p-chlorophenoxy)-acrolein, hydroquinonebis-(b -aldehydovinyl)-ether, and b -(nitrophenoxy)-acrolein; (3) as in (2) but using sodium methylate as basic agent; (4) b -phenoxyacrolein is passed into a mixture of thiourea and sodium methylate in methanol, the solution concentrated and acidified yielding 2-mercaptopyrimidine; (5) phenol is reacted with 1-butine-3-one in ether containing pyridine or triethylamine and the resulting b -phenoxyvinyl methyl ketone condensed with guanidine carbonate with sodium hydroxide to give 2-amino-4-methylpyrimidine; (6) as in (5), but using 3-phenyl-1-propin-3-one to yield b -phenoxyvinyl phenyl ketone and then 2-amino-4-phenylpyrimidine; (7) as in (5), but using thiourea in methanolic sodium methylate instead of guanidine carbonate giving 2-mercapto-4-methylpyrimidine.